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15-deoxy-Δ¹²,¹⁴-PGJ₂ promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis.

ABSTRACT: Prostaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD₂ synthase is abundantly expressed in heart tissue and PGD₂ has recently been found to induce cardiomyocyte apoptosis. PGD₂ is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ¹²,¹⁴-PGJ₂ (15d-PGJ₂, present at high levels in ischemic myocardium) might cause cardiomyocyte damage.Using specific (ant)agonists we show that 15d-PGJ₂ induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ₂ enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ₂ (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling.We conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ₂ is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ₂-induced myocardial injury.

SUBMITTER: Koyani CN

PROVIDER: S-EPMC4008937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeIntrahepatic cholestasis is mainly caused by dysfunction of bile secretion and has limited effective treatment. Rosiglitazone is a synthetic agonist of PPARγ, whose endogenous agonist is 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2 ). Reticulon 4B (Nogo-B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice.Experimental approachWild-type, hepatocyte-specific PPARγ or Nogo-B knockout mice received intragastric administration of α-naphthylisothiocyanate (ANIT) and/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non-PBC controls were analysed for cholestasis-related parameters.Key resultsRosiglitazone prevented wild type, but not hepatocyte-specific PPARγ deficient mice from developing ANIT-induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo-B knockout provided protection similar to that of rosiglitazone treatment. ANIT-induced intrahepatic cholestasis decreased 15d-PGJ2 but increased Nogo-B in serum, and both were corrected by rosiglitazone. Nogo-B deficiency in the liver increased 15d-PGJ2 production, thereby activating expression of PPARγ and bile homeostatic proteins. Rosiglitazone and Nogo-B deficiency also alleviated cholestasis-associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d-PGJ2 and increased Nogo-B levels were significantly correlated with classical cholestatic markers.Conclusions and implicationsLevels of 15d-PGJ2 and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis-associated dyslipidemia.

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15-deoxy-Δ¹²,¹⁴-PGJ₂ promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis.

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